Our proposal aims to improve the efficacy of intraoperative radiation therapy (IORT) for the treatment of early stage breast cancer, to investigate the immune effects of breast radiation therapy, and to evaluate the comparative effectiveness and costs of an advanced form of breast IORT. IORT is an emerging alternative to whole breast irradiation (WBI), but its current embodiment has several deficiencies including the lack of imaging for target delineation and planning, and poor dosimetry due to the use of low-energy photons. We have leveraged advanced CT-guided, high dose-rate brachytherapy techniques to develop Precision Breast IORT (PB-IORT), a novel method that improves upon conventional breast IORT (CB-IORT) through customized, three-dimensional treatment planning and delivery for higher dose, accurate, individualized IORT that better targets the breast tissue. Our phase I safety and feasibility trial established that PB-IORT can safely deliver 12.5 Gy (roughly twice the dose of CB-IORT) to the at-risk breast tissue. We will evaluate the efficacy of PB-IORT in a multi-center Phase II trial that will assess important clinical and immunologic outcomes and will provide data to enable comparative effectiveness studies, addressing the following specific aims: Aim 1: To determine the efficacy of PB-IORT on 5-year local breast cancer recurrence rates. Because PB-IORT delivers a more accurate and higher dose than CB-IORT, we hypothesize that PB-IORT will result in lower rates of local tumor recurrence than CB- IORT, and similar rates compared to WBI. We will also characterize the cosmetic and quality of life outcomes and mammographic changes after PB-IORT. Aim 2: To evaluate the effects of PB-IORT on the immune system. We will use blood samples from patients treated with PB-IORT and a comparison cohort of WBI-treated to provide fundamental insights into the impact of RT volume and fractionation on immune-suppressive effects of breast RT, determining whether IORT can avoid the immune-suppressive effects of WBI. Aim 3: To evaluate the comparative effectiveness of PB-IORT compared to treatment alternatives. We will apply Markov modeling methods to compare PB-IORT to all other options for breast RT. We will consider how variations in patient preference and recurrence risk impact outcomes and how reimbursement rates would impact cost effectiveness. We will evaluate the costs of PB-IORT using time-driven activity-based costing to inform value-based reimbursement decisions, providing policy-relevant evidence important for dissemination. Our two-institution team provides a foundation for expansion of PB-IORT to facilities without an integrated image-guided brachytherapy suite. As a technically optimized form of IORT, PB-IORT may may ultimately improve patient outcomes and satisfy patient demand by providing an optimized, more effective form of IORT that will reduce recurrences compared to CB-IORT, and will better preserve immune function compared to WBI while reducing health care costs.